Onset or treatment of audiological disorders such as dyslexia and tinnitus are associated with changes in neural activity in auditory cortex. Although a causal link has not been established between auditory cortical plasticity and such pathologies, experimental work has shown that auditory cortical plasticity can give rise to changes in perception, which may underlie pathological phenotypes and their disappearance through treatment. By learning how to replicate the conditions under which auditory cortical plasticity occurs, then, we will improve our understanding of the etiology of audiological and communication disorders and may even be able to induce plasticity for therapeutic purposes. This research proposal takes a step toward that goal by elucidating whether norepinephrine (NE), a neuromodulator released in contexts known to be conducive to plasticity, is necessary for auditory cortical plasticity. The different characters of plasticity across the lifetime necessitate a two-pronged approach that addresses the importance of NE for plasticity in development as well as adulthood. Specific aim 1 will assess whether NE is necessary for establishment of normal auditory cortical responses during a developmental critical period. We will investigate this by exposing normal mice and genetically manipulated mice that are NE-deficient from birth to a biased acoustic environment during their auditory critical periods, then using electrophysiological methods to map the response properties of their auditory cortices once they reach adulthood. Determining whether the environmental bias is reflected in the organization of the NE-deficient cortex will reveal whether NE is necessary for developmental plasticity in auditory cortex. Specific aim 2 will evaluate whether forebrain NE is necessary for auditory cortical plasticity in the less malleable adult brain by attempting to drive arousal-induced plasticity in animals with chemically lesioned forebrain noradrenergic systems. The extent to which we are successful in driving plasticity will indicate the strength of NE's role in initiating changes in response properties. This work will provide insight into the molecular environment in which plasticity occurs and lays a foundation for future studies of the cellular basis of learning and memory. PUBLIC HEALTH RELEVANCE: Alteration of the response properties of neurons in the auditory cortex has been associated with changes in perceptual abilities, but the molecular mechanisms that permit such neural changes have not been fully described. This research proposal will elucidate whether the neuromodulator norepinephrine, whose release has been associated with enduring neurophysiological changes in some systems, is necessary for experience- dependent plasticity in the auditory cortex. This work may ultimately advance our understanding of the etiology of hearing and communication disorders, and perhaps point toward novel therapies for the treatment of such disorders.